Selective degradation of 16-methyl-17-oh-20-keto steroids



United States Patent 3,539,598 SELECTIVE DEGRADATION OF 16-METHYL-17-OH-20-KETO STEROIDS Marcel Gut, Worcester, Mass., assignor toPhytogen Products, Inc., Mamaroneck, N.Y., a corporation of Delaware NoDrawing. Filed May 29, 1967, Ser. No. 642,163 Int. Cl. C07c 169/20 U.S.Cl. 260--397.3 4 Claims ABSTRACT OF THE DISCLOSURE The present inventiondescribes a selective degradation of 16-methyl-17-OH-20-keto steroidwith alkali metal bismuthate. The resulting l 6-methyl-l7-keto steroidsof the following formula are novel compounds.

keto steroids. The compounds may be represented by the followingformula:

R1 ll XisHorF OH OH R2- OHa R1 may be --H, O or -w OH:

B: may be 0, H2, OH

X may be F, 11

These compounds can be formed from known and available precursors byfirst introducing the 9a-fluoro when desired, and the 16-methyl groupinto an appropriate l7a-hydr0xy, 20-keto or hydroxy pregnane compound,then efiecting the present degradation reaction. Thus, dexamethasone canbe degraded with alkali metal bismuthate according to practice of thisinvention into the desired steroids.

"ice

The primary 17-ketosteroids obtained from the present reaction can beconverted to other derivatives by applying well-known, even conventionalreactions. Thus the primary product from the degradation ofdexamethasone ((1) 115 hydroxy 9a fiuoro-l6a-methylandrosta-l,4-diene-3,l7-dione) can be converted to a 17fi-hydroxyl derivative ((11)11/3,l7fl-dihydroxy-9u-fiuoro-16u-methylandrosta-1,4dien-3-one) by aconventional sodium borohydride reduction, which is in this caseselective to the extent that A -3-ketone moiety is attacked to a minordegree. Moreover, the same primary degradation product (I) is readilyoxidized to 9a-fiuoro-16a-methylandrosta- 1,4-diene-3,l1,17-trione (III)with chromium trioxide in aqueous acetic acid. This very same compoundcan be formed by direct degradation of 1704-, 21-dihydroxyocfluoro 16amethyl pregna 1,4-diene-3,11,20-trione. By employing l6a-methylprednisone and 16a-methyl prednisolone as starting materials, the17-keto pair of compounds (without the 9a-fluoro substituent) (Va, Vb)may be obtained. Reduction of either one of the pair of leads to17/3-dihydroxy-16wmethyl-androsta-l,4- dien-3-one (VIa, b). Similarly,the 16a-methyl-A -derivative of substance S on degradation gives aproduct with no oxygen function at position 11. (This compound is,however, not quite so desirable because of slightly higherandrogenicity.) Other methods are known to the art for effecting similardegradations. For example, chromic acid degradation is known to convertthe dihydroxyacetone side chain of the corticoids directly to theappropriate 17-keto steroids. Such reaction lacks selectivity, sincesecondary alcohol functions elsewhere in the molecule will beco-oxidized, and double bonds may be attacked. Consequently, for lack ofselectivity, the yields of the desired substance are low. Other knownmethods of degradation such as periodate oxidation and use of leadtetra-acetate suffer from a similar lack of selectivity in degradationof a highly substituted steroid molecule.

The present method of degradation employs an alkali metal (e.g. sodium)bismuthate. Aqueous acetic acid has been found to be an excellent mediumfor this reaction. It may be noted that the reaction mixture is ratherheterogenic with only a minor portion of the steroid in solution andgood stirring is essential. The yields of degraded products areremarkably good.

The various reactions involved in preparation of the compounds of thepresent invention may be seen from the following formula sequence andare further illustrated by the examples which follow.

l NaBH;

r J 116 lfi cHs [:gIjom EXAMPLE I V1lB-hydroxy-9a-fiuoro-l6a-methylandosta-1,4-diene- 3,17-dione (I) Onepart of dexamethasone(115,17a-21-trihydroxy-9afiuoro-lfia-methyl-pregna-1,4-diene-3,20-dione)in 60 parts of 50% acetic acid was shaken overnight with 10 parts ofsodium bismuthate. The reaction mixture was cooled in an ice bath and 10parts of sodium bisulfite in parts of water added. Then 100 parts ofWater were added, and

finally concentrated hydrochloric acid added until the salts dissolved.This mixture was extracted with dichloromethane and the extracts werewashed successively with water, 2 N sodium carbonate, and water, thendried and concentrated. 0.8 part of crude crystals was isolated byfiltration, which on recrystallization from benzene-hexane gave apurified sample of (1) with M.P. 245249 C.

The infrared spectrum of this compound showed the following major bands:

EXAMPLE II 11/3,l7fi-dihydroxy-9u-fluoro-16oc-methyl-androsta-1,4-dion-3-one (II) 0.2 part of the degradation product (1) obtained inExample I was dissolved in 40 parts of methanol and reacted with 0.038part sodium borohydride, while cooled in a bath of ice and water. Afterone hour of reaction, a few drops of acetic acid were added and thereaction mixture concentrated in vacuo. The residue was extracted in hotbenzene. From the benzene extract Was obtained 0.2 part of whitecrystals, which on one recrystallization from ethyl acetate-hexaneafforded 0.17 part of material M.P. about 172 C.

The infrared spectrum of this compound showed the major peaks:

EXAMPLE III 9a-fiuoro-l6u-methylandrosta-1,4-diene-2,11,17-trione (III)To a solution of 1 part of (I) (11B-hydroxy-9a-fluoro-16amethylandrosta-1,4-diene-3,l7-dione) in 25 parts of acetic acid, wasadded slowly a solution of 0.4 part of chromium trioxide in 90% aceticacid (50 parts). After 5 /2 hours at room temperature (+25 the reactionmixture was poured into a large volume of water and extracted withether. The ether extract was washed with 2 N sodium hydroxide solution,saturated sodium chloride, dried and concentrated. The residue proved tobe a mixture, and could not be purified by crystallization. It waschromotographed in silica gel and eluted with benzeneethyl acetate. Fromthe chromatography product was obtained 0.5 g. of material with M.P.207210 C.

The infrared spectrum had the salient bands seriatim:

EXAMPLE IV 9a-fluoro-l6a-methylandrosta-1,4-diene-3,11,17-trione (III)By bismuthate degradation of 17OL-21-dlhyd1'OXy-9OL"fluoro-l6a-methylpregna-1,4-diene 3,11,20-trione (IV).

One part of (IV) in 60 parts of 50% acetic acid was shaken overnightwith 10 parts of sodium bismuthate. The reaction mixture was treated asdescribed in Example I. 0.82 part of crude crystals was isolated.Recrystallization from benzene-hexane gave a purified sample: M.P. 199-201 C. (0.67 part). No depression in melting point could be observedwhen admixed with (III), prepared via chromic acid oxidation of (I). Theinfrared spectrum of the degradation product was in all detailsidentical with (III) prepared via the chromic acid route (Example III).

It should be noted that (III) prepared via bismuthate degradation didnot need chromatography for purification, whereas the chromic acidproduct (Example III) did.

EXAMPLE v The following substances were degraded with sodium bismuthateexactly as described in Example I.

Starting material, 1 part Product obtained, parts (a)lfia-methylprednisone 1fia-methylandrosta-l,4'diene-3,11,-

l7-trione, 0.72 part. (b) lfia-methylprednisolone1IB-hydroxy-l6a-methy1andr0sta- 1,4-diene-3,17-dione, 0.78 part.16a-Methylandrosta-l,4dicnc-3,17-

dione, 0.81 part.

(c) 16a-methyl-A S which is:

17a,21-dihydr0xy-1G-methylpregna1,4-diene-3,20-dione.

EXAMPLE VI The following 17-ket0steroidal degradation products werereduced with sodium borohydride as described in Example II, with theexceptions in the amounts of sodium borohydride used as noted below:

What is claimed is:

1. The compound: 11fi,17Bdihydroxy-9u-fluoro-16umethylandrosta-1,4-diene-3-one.

2. The compound: 9a-fluoro-l6a-methylandrosta-1,4- diene-3,11,17-trione.

3. The compound: 1,4-diene-3,17-trione.

4. The compound: drosta-1,4diene-3-one.

1 1 p-hydroxy-16u-methylandrosta- 1 1p,175-dihydroxy-16a-methylan-References Cited UNITED STATES PATENTS 8/1966 Robinson et a1. 260-397.5

OTHER REFERENCES ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.260397.45

